Progesterone modulates brain-derived neurotrophic factor and choline acetyltrans

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Exp Neurol. 2006 Exp Neurol. 2006 Oct 16

Progesterone modulates brain-derived neurotrophic factor and choline

acetyltransferase in degenerating Wobbler motoneurons.

lle MC, Garay L, S, Saravia F, Labombarda F,

Guennoun R, Schumacher M, De Nicola AF.

Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y

Medicina Experimental, and Dep. of Biochemistry, Faculty of

Medicine, University of Buenos Aires, Argentina.

Progesterone (PROG) shows neuroprotective effects in nervous system

diseases. The Wobbler mouse, a model of motoneuron degeneration,

suffers a mutation of the Vsp154 gene on chromosome 11 leading to

motoneuron vacuolation and astrocytosis of the spinal cord. Previous

work has demonstrated beneficial effects of PROG in the Wobbler

mouse.

As an extension of this work, we now studied steroid effects on

neuronal brain-derived neurotrophic factor (BDNF) mRNA and protein,

on choline acetyltransferase (ChAT) immunoreactivity (IR) and

activity in the spinal cord, and on recovery of muscle atrophy.

Wobbler mice received implants of PROG pellets (20 mg) at 6 and 10

weeks of age and were killed at 14 weeks. In situ hybridization for

BDNF mRNA demonstrated that grain density in large (>600 mum(2)) and

medium size (<600 mum(2)) ventral horn neurons was decreased in

untreated Wobblers, whereas PROG treatment increased BDNF mRNA in

both neuronal types.

PROG also induced a subcellular redistribution of BDNF protein,

which in controls and steroid-naive Wobblers showed a predominant

perinuclear and nucleolar location, whereas after PROG treatment, it

was detected in cytoplasmic aggregates. ChAT activity was reduced by

55.3% in muscles of untreated Wobbler mice, whereas a significant

increment was obtained after PROG treatment.

Wobblers also showed reduced number of ChAT positive motoneurons,

but this number was restored to normal by PROG. Finally, the

pronounced biceps atrophy of steroid-naive Wobbler mice was slightly

but significantly increased by PROG-treatment.

Considering the important role played by neurotrophins on neuronal

function, changes in BDNF might be part of the PROG activated-

pathways to provide neuroprotection and re-establish

neurotransmission and neuromuscular function in this degeneration

model.